This invention relates to a novel compound for treating or preventing diseases associated with the deposition of β-amyloid peptide in the brain, such as Alzheimer's disease, or of preventing or delaying the onset of dementia associated with such diseases.
Alzheimer's disease (AD) is the most prevalent form of dementia. Its diagnosis is described in the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., published by the American Psychiatric Association (DSM-IV). It is a neurodegenerative disorder, clinically characterized by progressive loss of memory and general cognitive function, and pathologically characterized by the deposition of extracellular proteinaceous plaques in the cortical and associative brain regions of sufferers. These plaques mainly comprise fibrillar aggregates of β-amyloid peptide (Aβ). Aβ is formed from amyloid precursor protein (APP) via separate intracellular proteolytic events involving the enzymes β-secretase and γ-secretase (see Selkoe, Physiol. Rev., 81(2), 741-766 (2001). Variability in the site of the proteolysis mediated by γ-secretase results in Aβ of varying chain length, e.g. Aβ(1-38), Aβ(1-40) and Aβ(1-42). N-terminal truncations such as Aβ(4-42) are also found in the brain, possibly as a result of variability in the site of proteolysis mediated by 3-secretase. After secretion into the extracellular medium, Aβ forms initially-soluble aggregates which are widely believed to be the key neurotoxic agents in AD (see Gong et al, PNAS, 100 (2003), 10417-22), and which ultimately result in the insoluble deposits and dense neuritic plaques which are the pathological characteristics of AD.
Other dementing conditions associated with deposition of Aβ in the brain include cerebral amyloid angiopathy, hereditary cerebral haemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.
The role of secretases, including that of γ-secretase, in the processing of amyloid precursor protein (APP) to form Aβ is well documented in the literature, and so inhibiting the processing of APP by γ-secretase is recognized as a likely means of treating or preventing AD and related conditions (a recent review of activity in this area is provided by Garofalo, Expert Opin. Ther. Patents (2008) 18(7), 693-703). However, attempts to develop such a treatment have been hampered by the fact that γ-secretase is active towards a number of different transmembrane proteins in addition to APP (for a review, see Pollack and Lewis, Current Opinion in Investigational Drugs (2005), 6(1), 35-47), with the result that inhibition of γ-secretase can lead to unwanted side effects as well as the desired interruption of APP processing. In particular, γ-secretase plays a crucial role in the Notch cell-signaling process, which itself plays a crucial role in cell-fate determination. The Notch receptor protein is a transmembrane protein which, in response to activation by the relevant ligand, undergoes intramembranous cleavage by γ-secretase, releasing the Notch intracellular domain (NICD) which can then migrate to the cell nucleus and modulate gene transcriptions (Pollack and Lewis, supra). An example of cell-fate determination influenced by Notch is the differentiation of proliferative epithelial cells in the gastro-intestinal (GI) tract, with the result that suppression of Notch processing leads to intestinal goblet cell metaplasia and severe GI toxicity (Searfoss et al, J. Biol. Chem. (2003), 278(46), 46107-46116; Wang et al, J. Biol. Chem. (2004), 279(13), 12876-12882; Milano et al, Toxicological Sciences, (2004), 82, 341-358; and Van Es et al, Nature (2005), 435, 959-963).
There is therefore a need for a means of inhibiting the processing of APP that has minimal effect on the processing of Notch. Although there are a few reports of γ-secretase inhibitors showing selectivity for APP processing over Notch processing (see Garofolo, supra; and Petit et al, J. Neuroscience (2003), 74, 370-377), none has so far led to a viable treatment for AD. Furthermore, the present investigators have found that certain compounds which show selectivity for APP processing over Notch processing in vitro can still cause GI toxicity in vivo, particularly when administered to higher species such as primates. There is therefore an ongoing need for improved methods for inhibiting APP processing without incurring significant Notch-related GI toxicity.
The present invention is directed to a novel trifluoromethylsulfonamide derivative which inhibits the processing of APP by the putative γ-secretase and thus is useful in the treatment or prevention of AD. This compound possesses pharmacokinetic properties in higher species (rhesus) which are favorable for dosing on an intermittent dosing regiment (e.g., once weekly). When dosed on such a regiment the compound exhibits significant and continuous Aβ lowering without the manifestation of Notch associated gastrointestinal toxicity for extended periods, e.g., 7 days.